Peter Kramer and Antidepressants - Oy!

I was going to have a relaxing evening tonight, recovering from my trip to Chicago and a very busy four days at the NAMI national convention, plus two days in airports. I was saving tomorrow for gradually settling back into my blog with some of cool stuff I came across in Chicago. Then I encountered a piece in the July 9 NY Times by Peter Kramer, entitled, “In Defense of Antidepressants.”

Okay, before we start, here’s an extract from my lead mcmanweb article on antidepressants:

The strongest scientific evidence we have is not how well antidepressants work, but how badly they perform and how harmful they may be to certain individuals. Here's the low-down:

Two meta-analyses of the FDA clinical trials conducted by Irving Kirsch of the University of Connecticut in the late 1990s-early 2000s of Pharma-sponsored clinical trials - including ones not published - in the FDA database found that antidepressants worked only marginally better against depression than placebos. There have been a number of expert rebuttals to these findings, but no actual study to contradict Kirsch.

The article reports on the most authoritative real-world study on antidepressants, the NIMH-underwritten STAR*D from the mid-2000s. We continue from my article:

Commenting on STAR*D, in a 2009 blog, Nassir Ghaemi MD of Tufts University noted that:

“Even if antidepressants worked in the short term (2 months, which is also what the meta-analysis assessed), one-half of patients who stayed on them relapsed into depression within one year. At the one year outcome, only about 25% of patients actually had remained well on and tolerated an antidepressant, much below the levels most clinicians seem to feel occurs in their clinical experience.”

One in four! According to the best data we have, just one in four individuals treated with an antidepressant get well and stay well. And this was in the best possible care setting. Is your clinician aware of this? Probably not.

Neither is Peter Kramer of Brown University. Dr Kramer is the author of the 1993 “Listening to Prozac,” which is largely a product of the time, back when we all trusted Pharma a lot more than we do now. We have learned a lot since then, including the fact that these drugs can be highly destabilizing to individuals with bipolar and with depressions that cycle like bipolar.

But Dr Kramer in his NY Times article mentions neither STAR*D nor the obvious risks of taking an antidepressant. Huh?

Dr Kramer’s defense of antidepressants is specious and drearily unoriginal, one based on a speculative nitpicking of Kirsh. Back in a newsletter piece I did nine years ago, I referred to this as the “Van Meegeren Defense.”

Prior to World War II, Han Van Meegeren earned a nice living for himself selling bad forgeries of Vermeers. When World War II came along, one of Van Meegeren’s customers turned out to Reichsmarshall Hermann Goring. After the War, Van Meegeren was arrested for collaborating with the Nazis and charged with treason.

Here’s the part of the story I love: Van Meegeren’s defense to selling cultural treasures to the Nazis was that they were not real Vermeers, but his own forgeries. In other words, he had to convince the court that he had cheated.

Okay, now that you “get” the Van Meegeren Defense, here is what Dr Kramer has to say in his NY Times article:

Consequently, companies rushing to get medications to market have had an incentive to run quick, sloppy trials.

In other words, to cheat. What Dr Kramer is saying is that clinical antidepressants trials sponsored by drug companies might have yielded better results had they stuck to protocol and included only patients most likely to respond to antidepressants, namely those with severe depression. In effect, the drug companies, in their haste to recruit patients, probably included a substantial number of likely non-responders, namely those with milder forms of depression or those who plain lied to get into a trial. Thus, according to Kramer:

Often subjects who don’t really have depression are included — and (no surprise) weeks down the road they are not depressed. People may exaggerate their symptoms to get free care or incentive payments offered in trials. Other, perfectly honest subjects participate when they are at their worst and then spontaneously return to their usual, lower, level of depression.

As I stated earlier, this is not a new explanation. I first came across it soon after Kirsch’s second meta-analysis was published in 2002. Basically, academic critics acknowledged that Kirsch had made a bullet-proof case based on the evidence. So, then, how to explain the evidence?

Ah, the Van Meegeren Defense. In other words, if the drug companies had not cheated to begin with, maybe, just maybe, the results might - just might - have come out more in their favor.

It’s all speculation, of course. The only real way to counter Kirsh’s bullet-proof evidence is with bullet-proof evidence of one’s own. And while we're at it, to come up with an authoritative real-world study to counter the STAR*D real-world study.

There are many nuances to the antidepressant debate, and in all likelihood these meds work for a certain subpopulation of depressed patients (if we only knew who they were), but - again - this is speculation, not science.

The bottom line is the most convincing evidence we have on the (non)efficacy of antidepressants comes from Kirsch and STAR*D. The only counter-evidence is recycled speculation, Kramer-style.

***
Robert Whitaker on his Mad in America blog picks Kramer apart in far greater detail, concluding with:

On Sunday, in this essay "In Defense of Antidepressants," the American public has been treated to yet another dose of misinformation. 

Are Antidepressants Bad for You? - Part V

We left off with the proposition that if you walk in the door with depressive symptoms, your clinician has at least four chances to get it wrong and only one chance to get it right. Your condition may be posing as classic depression, but may in fact be something completely different, namely:

• The depressive phase of bipolar.
• A highly recurrent depression, having more in common with bipolar than classic unipolar depression.
• A personality disorder, such as borderline.
• Your true personality - your "normal" baseline self - rather than an exception to your personality.

Chances are your clinician is missing this. He or she is thinking: Looks like depression, must be depression, ergo antidepressant. But we know that antidepressants can make bipolar worse. Likewise, there is good support for the proposition that people with highly recurrent depression need to avoid them, as well. And even a caveman's dumb half-brother knows that there is no med for changing a personality.

Clearly, most of you reading this should never have been put on an antidepressant in the first place. A placebo would have worked a lot better and with no side effects. At least you wouldn't be feeling worse. But maybe you're one of the "lucky" ones, with classic depression. An antidepressant for depression is just what the doctor ordered, right? Um, uh, define depression. This edited extract from a Feb blog post elaborates:

The DSM-II of 1968 viewed depression as both separate from (in the sense of “depressive neurosis”) and as part of manic-depression (in the sense of “manic depressive illness, depressed type”) and tied into anxiety (in the form of “involuted melancholia” and as the driving force of “neurosis”) as well as embedded into personality (as in “cyclothymic personality disorder characterized by depression”).

Moreover, the DSM-II distinguished between depression seen as a result of the mysterious biology of the brain (“endogenous”) and depression seen to be caused by a reaction to events (“exogenous”).

The DSM-III of 1980 replaced all that with a monolithic view of unipolar depression, separating it out from manic-depression and anxiety and personality and doing away with the endogenous-exogenous distinction. Instead, for the first time, we were treated to the famous and extraordinarily arbitrary nine-item symptom checklist.

In my book, "Living Well with Depression and Bipolar Disorder," I cite a 2004 article by Gordon Parker MD, PhD of the University of New South Wales in support of the proposition that this one-size-fits-all view of depression results in clinical trials that indiscriminately lump all patients together, with no regard to critical distinctions that may spell the difference between success and failure.

We know for instance that an SSRI such as Paxil gets 50 percent of patients with “major depression” 50 percent better over a period of about six weeks. This is good enough for the drug companies, who now have a license to print money, but what about the patients? Who wants a 50 percent chance of success? And who wants to be just 50 percent better?

What do we know about Paxil, anyway? Does it work better on a patient whose depression is marked by sadness? If so, is it possible to target this group of patients? Maybe then we would be seeing 80 percent of these individuals getting 80 percent better.

And try this on for size. Maybe a patient whose main feature is lack of motivation (about which the DSM has nothing to say) would benefit from something else, as would depression brought on by stress (the type of “exogenous” depression axed from the DSM-III). Maybe these drugs don’t exist. Maybe Pharma would be encouraged to develop them. As Dr Parker in a 2007 piece concludes:

Depression is a diagnosis that will remain a non-specific "catch all" until common sense brings current confusion to order. As the American journalist Ed Murrow observed in another context: "Anyone who isn't confused doesn't really understand the situation."

***

To tie this in a bow: It's not enough that a clinician accurately diagnoses depression, as the term is at best an umbrella designation, the way "infectious disease" is an umbrella designation. Yes, an antibiotic may be useful against many types of infectious disease, but we cannot make the same claim for an antidepressant for the zillion different things going on inside our brains that we happen to lump together as depression. The best we can say for antidepressants is that they work for some individuals with DSM depression. The catch is we don't know in advance who these people are.

More to come ...

Previous articles

Are Antidepressants Bad for You?
Are Antidepressants Bad for You? - Part II
Are Antidepressants Bad for You? - Part III
Are Antidepressants Bad for You? - Part IV 

Are Antidepressants Bad for You? - Part IV

The story so far:

In his blog Mad in America, author Robert Whitaker drew attention to a recently published review article by Fava and Offidani that came to this startling conclusion:

When we prolong treatment [with antidepressants] over 6–9 months we may recruit processes that oppose the initial acute effects of antidepressant drugs (loss of clinical effects). We may also propel the illness to a malignant and treatment-unresponsive course that may take the form of resistance or episode acceleration.

In support of their view, Fava and Offidani cite studies that show that staying on antidepressants longer than three months has no effect at reducing the risk of recurrence and may, in fact, make the illness worse. What may be occurring, they hypothesize, is "oppositional tolerance," where, over time, the brain pushes back against the antidepressant.

But the authors also note that our lack of scientific understanding of depression leaves room for interpretation.

In his book, "Anatomy of an Epidemic," Whitaker helps us out by noting that, historically, depression had been regarded as a rare illness with a good prognosis. Then antidepressants became the rage. Despite this, too many patients only seemed to be getting worse over the long haul rather than better. According to Whitaker, instead of questioning the med, psychiatry questioned the diagnosis. Overnight, the new consensus was that antidepressants are okay, but the illness is highly prevalent with a poor prognosis.

Thus, ironically, depression became an epidemic.

But what if depression is the wrong name for this epidemic? What if most of what we are observing is not clinical depression at all? And what if not all depressions are the same? These are questions I have been asking on this blog and elsewhere. 

Let's start with the obvious, with the unipolar/bipolar distinction. All too often, people with bipolar walk in the door depressed, are misdiagnosed with unipolar depression, and given an antidepressant. If they are lucky (as I was), the antidepressant will quickly flip them into mania, which will put even the dumbest clinician on notice to change both the diagnosis and treatment.

If the patient is unlucky (as many are), the antidepressant may initially make that individual feel better before feeling worse. Then that individual endures the heartbreak and frustration of being tried on one antidepressant after another, years on end. Ten or 11 years later (the time it usually takes to make an accurate bipolar II diagnosis), a smart clinician finally considers the obvious.

There is now widespread agreement that an antidepressant, even with a concomitant mood stabilizer, does nothing (as a general rule) to improve bipolar. Moreover, we know these meds run a high risk of making it worse.

There is also an emerging consensus that this may be the case for many so-called unipolar depressions, as well. These are individuals that Goodwin and Jamison in their second edition to "Manic-Depressive Illness" characterize as "highly recurrent." In other words, there is a cycling nature to the course of their illness, much like bipolar, even if the "ups" fall well short of mania or hypomania. But give these individuals an antidepressant and that may change. In effect, an antidepressant may turn an unsuspecting unipolar into a bipolar, a point that Whitaker visits in Chapter Nine of his book.

Obviously, psychiatry needs to light a match to the DSM and start over. Whether one calls highly recurrent depression a new form of depression or a new form of bipolar hardly matters, so long as clinicians are put on notice to think twice before prescribing an antidepressant. But that is not the end of the story. Four years ago, I had this to report, from a lecture delivered by Joel Paris of the University of Toronto at the 2006 APA:

In true Axis I depression, Dr Paris explained, when patients come out of a depression, they are nice people again. Individuals with personality disorders, by contrast, can come out of a depression and still have problems with life. Unfortunately, clinicians prefer not to want to hear about personality. It means trouble. They would rather throw more meds at the problem.

Dr Paris was talking about borderline personality disorder, which is often misdiagnosed as a mood disorder. With psychiatry at long last showing signs of breaking off its love affair with Pharma (thanks to psychiatric meds losing their patent protection), personality disorders are starting to get a lot more respect.

Let's take this a step further. Suppose, in some cases, that depression itself could be considered a personality disorder, as some experts are proposing (a rather controversial view) or (much less controversially) as part of one's baseline temperament? (See my January blog post on this.) In this context, depression is a natural (and possibly even healthy) part of a person's personality rather than a deviation from from one's normal healthy state.

To wrap this up for now, imagine a patient walking into a psychiatrist's office manifesting depressive symptoms. Assuming the cause is not physical (such as a thyroid condition) or neurological (such as dementia), we have five (not necessarily mutually exclusive) possibilities, namely:

1. Classic unipolar depression.
2. The depressive phase of bipolar disorder, either I or II or cyclothymia.
3. Something in between, or overlapping with, classic depression and classic bipolar.
4. A personality disorder, such as borderline.
5. A personality trait or temperament.

Five possibilities. Four chances to get it wrong. Only one chance to get it right. Is it any wonder that doctors get such bad results or that patients undergo so much misery? But even if the clinician spins the wheel correctly, we are talking numerous sub-possibilities within the one possibility that holds out promise. In other words, even more chances to get it wrong.

Stop this game of antidepressant roulette right now! one wants to cry out.

Next: The game goes on, anyway ...

Previous articles

Are Antidepressants Bad for You?
Are Antidepressants Bad for You? - Part II
Are Antidepressants Bad for You? - Part III

Are Antidepressants Bad for You? - Part III

Yesterday, we looked at a review article by Giovanni Fava and Emanuela Offidani that introduced the idea of "oppositional tolerance" in regard to long-term antidepressant use. According to the authors, the few long-term studies we have indicate a three-month limit to antidepressant treatment. Staying on these meds any longer appears to have no impact on avoiding a recurrence. Indeed, in some cases, long-term use may make our depressions worse and set us up for future episodes.

The reason for this, the authors hypothesize, is that as our brains build up a tolerance to these meds, various processes are set in motion that counteract the drug's initial effect which in turn may "propel the illness to a more malignant and treatment-unresponsive course."

The authors note, however, that oppositional tolerance needs to be considered in the broader context of psychiatry's highly suspect diagnostic criteria for mood disorders. This portion of the conversation begins in Robert Whitaker's "Anatomy of an Epidemic":

In Chapter Eight, Whitaker cites community surveys from the 1930s and 40s that found "fewer than one in a thousand adults suffered an episode of clinical depression each year." According to Charlotte Silverman, author of "The Epidemiology of Depression" (1968), and others, depression was primarily an "ailment of middle aged and older persons." Most of the "depressed-only" patients observed by Emil Kraepelin in the early twentieth century experienced just a single episode of depression and only 13 percent had three or more episodes. Even as late as 1972, Guze and Robins of Washington University (St Louis) noted that only one in ten became chronically ill.

Then came the antidepressant era in full force. For some patients, these meds proved to be magic bullets, at least in the early going. But it wasn't long before researchers began reporting on their inordinately high relapse rates (the scientific term is "Prozac poop-out"). According to Whitaker, psychiatry decided this had to do with the course of the illness rather than the effects of the drug. Overnight, psychiatry changed its party line to the effect that depression was everywhere, and that the old epidemiological studies were "flawed." In the words of the American Psychiatric Association, "depression is a highly recurrent and pernicious disorder."

Says Whitaker: "In the short span of forty years depression had been utterly transformed," going from a rare illness with good outcomes to an epidemic that kept visiting havoc its victims.

Giovanni Fava was a lone voice back in 1994 when he dared suggest in an editorial that we need to be paying attention to the man behind the curtain, wondering if meds "may actually worsen, at least in some cases, the progression of the illness which they are supposed to treat." Since Fava was merely posing this as a hypothetical he was easy to dismiss. Whitaker asserts that Fava's concerns "needed to be hushed up," but the APA is not exactly a Star Chamber.

Sixteen years later, Fava is still beating the drum, this time far less tentatively. Fittingly, it is Whitaker in his blog Mad in America who drew attention to Fava's latest contribution. Clearly Whitaker is onto something. In his book, he makes the telling point that if our meds worked as well as Pharma would have us believe, then we wouldn't have illnesses like depression to kick around anymore. Or, at the very least, thanks to treatment, depression would be very rare and relatively benign. This is a point that other commentators have raised as well, including David Healy of Cardiff University.

Instead, in the face of overwhelming evidence that depression has - defiantly, it seems - refused to yield to repeated antidepressant bombardment, psychiatry has changed its tune on the illness. Suddenly, it's everywhere and is highly malignant. Again, Whitaker and Healy and others are in harmony.

Do you see the dots starting to connect? Namely: Problematic meds to treat a vaguely defined illness advanced by those with strong monetary interests, leading to this major fallacy - If it's depression, then one must always treat it with an antidepressant.

But what if it's NOT depression, even if it looks like depression? Or what if not all depressions are the same? And who, precisely, are these people, anyway, these anomalies of psychiatry, who are put on meds that may make them worse rather than better? Why are they being lumped with everyone else?

These are questions that badly need to be asked, that hardly anyone seems to be asking.

Next: We ask the questions ...

Are Antidepressants Bad for You? - Part II

Yesterday focused on an important review article by Giovanni Fava of the University of Bologna (Emanuela Offidani, co-author), brought to my attention by Robert Whitaker on his blog, Mad in America. In the review article, Fava and Offidani indicate that long-term use of antidepressant drugs in some cases may actually worsen the outcome of depression. But they also suggest that bad outcomes may have a lot to do with our simplistic notion of depression, which only encourages equally simplistic treatments.

Let's start at the beginning ...

According to Fava and Offidani, antidepressants are much better suited to treating the episode rather than the illness. Thus, if you are feeling depressed, there is a reasonable chance that your antidepressant may boot you out of your current state - for a little while, anyway. The evidence that antidepressants will keep another depression from occurring, however, is far more problematic.

For instance, a 1998 study found that patients on Prozac fared nearly twice as well as those in the placebo group (26 percent relapse vs 48 percent), but only at the 24-week point. After 62 weeks the two groups relapsed about equally. Other studies show relapse rates in the 46 to 65 percent range over one year.

Meanwhile, in some individuals (30 percent in one study, 7 percent in another), depression scores went up among those on an antidepressant rather than down. Also, studies have found that antidepressants appear to increase - not decrease - the frequency of recurrences, and that they increase depression symptoms in those being treated for anxiety.

We know there is a high risk of antidepressants causing bipolar patients to flip into mania or speeding up cycling, but there is also the possibility that these meds may also increase the rate of depressive relapse in this same population.

What is going on?

In their review article, Fava and Offadani devote a lot of attention to the tolerance factor. Thus, in a 1995 study conducted by Fava, patients who relapsed on Prozac at 20 mg responded to Prozac at 40 mg. A related phenomena is "resistance," when a med doesn't work when restarted after it had previously been effective. Percentages from various resistance studies range from 4 to 38 percent. Then there is "discontinuation syndrome," such as headache or sleep disturbance soon after the med is withdrawn. This occurs with far greater frequency in the shorter half-life meds such as Paxil.

The unifying theme, the authors suggest is "oppositional tolerance." In their own words:

According to this model, continued drug treatment may recruit processes that oppose the initial acute effects of a drug or of receptor alterations ... Use of antidepressant drugs may also propel the illness to a more malignant and treatment-unresponsive course ...

We're entering the realm of hypothesis here, but what may be happening, according to the authors, is that the therapeutic modulations that antidepressants induce in the 5HT1A, 5HT1B, and 5HT2 serotonin receptors may, in certain cases, be triggering downstream effects inside the neuron "that are likely to affect the balance of serotonin receptors."

Or a similar result may occur via the HPA axis (the neuroendocrine loop that mediates fight-or-flight). In this scenario, enhanced 5HT1 neurotransmission may activate the HPA axis, which in turn may disturb serotonin receptor function. Stress figures mightily in depression, and while antidepressants may have a protective effect, in some cases there is the possibility of heightened sensitization.

The authors acknowledge there are no studies that prove oppositional tolerance, but the NIMH-underwritten STAR-D trials, they maintain, sheds light on the theory. In STAR-D, 3,600 patients were first tried on Celexa. Of these, 37 percent remitted. Those who didn't recover were tried on other antidepressants or various meds combinations in four successive stages. Sixty-seven percent of those who remained in the study eventually remitted, but owing to relapse the true figure was 43 percent. Thus, the very best that medicine could accomplish was squeeze out a measly 6 percent improvement in the initial recovery rate. Moreover, remission rates decreased after each treatment while relapse rates increased.

STAR-D most convincingly demonstrated that when the first or second antidepressant fails, there is little prospect of the third or fourth one proving to be the magic bullet. But was this due to a predisposition on the part of the individual patient or to the cumulative effects of repeated antidepressant administration? Fava and Offadani raise the possibility of the latter, saying that switching or augmenting meds "may propel depressive illness into a refractory phase, characterized by low remission, high relapse and high intolerance."

This sets up their conclusion:

When we prolong treatment over 6–9months we may recruit processes that oppose the initial acute effects of antidepressant drugs (loss of clinical effects). We may also propel the illness to a malignant and treatment-unresponsive course that may take the form of resistance or episode acceleration. When drug treatment ends, these processes may be unopposed and yield withdrawal symptoms and increased vulnerability to relapse. Such processes are not necessarily reversible. The more we switch or potentiate antidepressant drugs the more likely is oppositional tolerance to take place.

But they also pull their punch with this final sentence: 

The phenomena we have described, however, are difficult to interpret unless a precise diagnostic categorization of mood disturbances is made, taking into consideration both their longitudinal course, the unipolar/bipolar distinction and their subtypes.

Here, of course, is where the real discussion begins.

Next: The real discussion begins ...

Are Antidepressants Bad for You?

This is the eleventh in my series based on talking points raised by Robert Whitaker's eye-opening "Anatomy of an Epidemic."

We take a slight detour. A late Oct blog entry to Robert Whitaker's "Mad in America" contained this intriguing title: Do Antidepressants Worsen the Long-term Course of Depression? ...

The piece extracted some of the main points from a review article by Giovanni Fava of the University of Bologna. Here is Whitaker's summation:

• After six months of antidepressant treatment, the drugs "generally fail to protect" against a return of depressive symptoms. (In other words, maintenance treatment is ineffective, compared to placebo.)
• Two-thirds of patients maintained on antidepressants suffer from "residual symptoms," with "anxiety, insomnia, fatigue, cognitive impairment, and irritability the most commonly reported."
• As patients are switched from one antidepressant to another or to a polypharmacy regimen, their illness may be propelled "into a refractory phase, characterized by low remission, high relapse and high intolerance."
• Antidepressants increase the risk of a "switch" into mania, and thus into bipolar illness. Antidepressants also increase the risk that bipolar patients will become rapid cyclers, and that bipolar patients will develop a syndrome dubbed "Chronic Irritable Dysphoria."

Make no mistake, right from the get-go Fava very unambiguously sounds the alarm:

It was suggested that long-term use of antidepressant drugs may increase, in some cases, the biochemical vulnerability to depression and worsen its long-term outcome and symptomatic expression, decreasing both its likelihood of subsequent response to pharmacological treatment and the duration of symptom-free periods.

In summing up, he notes:

When we prolong treatment over 6–9months we may recruit processes that oppose the initial acute effects of antidepressant drugs (loss of clinical effects). We may also propel the illness to a malignant and treatment-unresponsive course that may take the form of resistance or episode acceleration. When drug treatment ends, these processes may be unopposed and yield withdrawal symptoms and increased vulnerability to relapse. Such processes are not necessarily reversible. The more we switch or potentiate antidepressant drugs the more likely is oppositional tolerance to take place.

But there is this important qualifier:

The phenomena we have described, however, are difficult to interpret unless a precise diagnostic categorization of mood disturbances is made, taking into consideration both their longitudinal course, the unipolar/bipolar distinction and their subtypes.

Dang! Nuances again.

Next: A look at the nuances ...

Wait! If You Read That Newsweek Article About How Antidepressants Don't Work and Are About to Flush Your Meds Down the Toilet, First Read This ...

I should have commented on this much earlier. Better late than never ...

A Jan 29 Newsweek cover story trumpeted, Why Antidepressants Don’t Work. There are many things not to like about antidepressants, including the fact that they are not magic bullets and often may make us worse rather than better. Indeed, if antidepressants were as effective as Pharma and psychiatry claim, depression would have gone the way of polio and small pox. Instead, it remains the leading cause of disability in the western world.

Nevertheless, a willing patient working with a smart clinician stands a fairly decent chance of getting somewhat or even a lot better on an antidepressant. And there is convincing data that a patient who stays on an antidepressant has a much better chance of avoiding relapse than one who doesn’t.

The best evidence we have points to the fact that antidepressants do work - only not for all of us and not as well as we wish they would. But, in their limited capacity, they do - actually - work.

So how can Newsweek be so irresponsible? The story begins with an equally irresponsible review article that appeared in the Jan 6 JAMA. Medical journals are notorious for publishing industry propaganda disguised as research. This one went the other way.

The JAMA article reports on a University of Pennsylvania meta-analysis that found that antidepressants were effective on patients with severe depression, but had little or no effect on those with mild or moderate depression. A meta-analysis pools previous studies and crunches the composite numbers. The catch is those putting together meta-analyses can be highly selective in which studies they decide to pool.

An article by Amy Tuteur MD in the Feb 8 Salon, How Did Journalists Get the Antidepressant Study So Wrong?, notes that of 141 random-controlled antidepressant trials the authors included only three involving a single SSRI medication, Paxil. (Three other trials included in the meta-analysis involved the rarely-used old-generation antidepressant imipramine.)

The selective weeding-out process seriously undermined the credibility of the meta-analysis, a fatal flaw the JAMA editors should have picked up. As Dr Tuteur points out, there were 23 trials that did not make the final cut. Of these, 15 of 17 showed antidepressants to be effective for mild to moderate depression.

In other words: “ALL the studies that demonstrated the effectiveness of antidepressants in mild to moderate depression were deliberately left out.”

More convincing evidence against antidepressants are two other meta-analyses cited in the Newsweek piece. These were conducted by Irving Kirsch PhD of the University of Connecticut. His second one, using all the antidepressant clinical trials the drug companies submitted to the FDA, found that those on the antidepressants fared only minimally better than those taking a placebo.

I recall emailing Dr Kirsch about this back in 2002. In other words, I suggested, antidepressants are nothing more than placebos with side effects. Dr Kirsch agreed with this.

Academic researchers managed to look silly attempting to rebut Dr Kirsch. Their main defense was that the stratospherically high placebo response rates (way higher than for say cancer drug trials) are the bane of psychiatric meds trials. They also pointed out that researchers, desperate to recruit patients into studies, may have allowed some in who didn’t meet their criteria for severe depression (a fantastic admission when you come to think of it, namely - we got bad results because in fact we cheated).

More credible was their argument that broad conclusions mask specific results - namely that for certain subpopulations these meds probably work like gangbusters. The problem is no one has identified this subpopulation. More on this in a minute.

Surprisingly, no one mentioned the obvious: A drug trial tests results on ONE drug only. In the real world, patients try a second drug if the first one doesn’t work. Various small studies showed that indeed it is worth not giving up after an initial failure.

The NIMH tested that proposition in a series of real-world trials called STAR*D, published in 2006. In the first round, about 50 percent of patients got better on Celexa. Of those who failed on Celexa, about a quarter to a third got better on another med or meds combination.

Thus, a 50-50 crapshoot turns into odds very much in your favor if you’re willing to play two rounds of pill roulette.

Third round success rates, however, were dismal - in single figures to very low double digits. In other words, after two failures, patients and clinicians need to be seriously rethinking their options, including revisiting the diagnosis.

What no one has seriously looked into is the fact that DSM depression may be completely wrong in the first place, that it is in fact a catch-all diagnosis for all manner of things going wrong in the brain.  In a recent blog piece, The Draft DSM-5 - Rip It Up and Start Over, Part II, I mention:


In my book, "Living Well with Depression and Bipolar Disorder," I cite a 2004 article by Gordon Parker MD, PhD of the University of New South Wales in support of the proposition that this one-size-fits-all view of depression results in clinical trials that indiscriminately lump all patients together, with no regard to critical distinctions that may spell the difference between success and failure.

Would, say, an SSRI such as Paxil work better for a melancholic depression and a dopamine-enhancer such as Wellbutrin work better for a low-energy depression? We’ll never know. The drug industry has no incentive to test for this sort of thing.

In an article on my mcmanweb site, I cite Frederick Goodwin MD, co-author of Manic-Depressive Illness, who informed me that most of the patients in STAR*D had recurrent depression, ie depressions that come and go. These depressions may have a lot more in common with bipolar than with unipolar chronic depression. One study found that nearly 40 percent of those diagnosed with unipolar depression in fact fall into that diagnostic Terra Incognita known as the bipolar spectrum.

These are patients who could conceivably respond better to mood stabilizers than antidepressants. The catch is the current DSM doesn’t recognize the bipolar spectrum and neither will the next one.


To conclude ...

Antidepressants DO work, but you will probably be a lot more satisfied with the results if you don’t expect too much of them. A lot of failures are the result of patients quitting too soon. The same can be said of clinicians who don’t know what they are doing.

If your first antidepressant fails, it is wise to try a second one, perhaps even a third.

But after your second one fails, it is wise to revisit your diagnosis. You may in fact have bipolar, or a type of unrecognized depression that has more in common with bipolar than unipolar. Or you may have a depressive temperament - part of your personality - that is better suited to talking therapy. Or you may have some kind of personality disorder (such as borderline) that definitely does require talking therapy.

Antidepressants leave a lot to be desired, but their greatest fault can be attributed to human error. These meds simply don’t work for certain types of depressions, and definitely not for a range of conditions that only superficially resemble depression. But for the right kind of depression, they probably work a lot better than we give them credit for. If we could only get researchers interested in looking into this.

Maybe then, Newsweek would have something to report.

Further reading from McManweb


When Your First Antidepressant Fails
When Your Second Antidepressant Fails
Clinical Trials - What the Drug Companies Don't Report

***

Coming soon - back to my DSM-5 report cards ...

David Healy: But Is It Depression?

In a recent (and still ongoing) series on Robert Spitzer and the DSM, I touched on some of the history of the difficulties in separating out the diagnosis of depression from both bipolar and anxiety (part of what Freudians used to call neurosis). A different historical perspective is offered by David Healy MD (pictured here) of the University of Wales. I originally published this in an email newsletter back in Nov, 2003, and it has been featured on my website since Dec, 2003:

Consider these scenarios: A patient back in the seventies complains of "nerves" or anxiety and is sent out the door with a tranquilizer (benzodiazepine) such as Librium or Valium. A few years later, that same patient might be asking for Xanax for her panic attack. In the mid-nineties, we have the same patient with the same symptoms telling her doctor she has depression. Today, the same patient is likely once again to complain about anxiety.

Much of the credit for how we understand ourselves goes to the pharmaceutical companies, even if we don’t take meds, David Healy MD of the University of Wales said in a grand rounds lecture at UCLA on Oct 28, 2003 and webcast the same day. Upjohn (since taken over by Pfizer) pioneered the concept of marketing the illness rather than the drug, capitalizing on the DSM-III’s reclassification of anxiety into several disorders to push Xanax for panic disorder. In the mid-eighties, as the benzodiazepines became a focus of concern, the SSRIs in development were first seen as non-habit-forming alternatives to tranquilizers before they were targeted to treat depression. More recently, the SSRIs are returning to their original purpose, with the drug companies spending up to $100 million a year to promote these meds as "anxiolytics" (thereby distinguishing them from the bad associations of tranquilizers).

A thorn in the side of the psychiatric establishment, Dr Healy is the author of "Let Them Eat Prozac" and a dozen other books, has published articles on the suicidal side effects that some patients can experience on antidepressants, has appeared as an expert witness in legal actions against Prozac and Paxil, and recently sued the University of Toronto for rescinding an employment offer. According to Dr Healy, in order to create new markets for its products, the pharmaceutical industry ghost-writes much of the literature that appears in mainstream psychiatric journals, mobilizes expert opinion, designs its own drug trials, engages in extensive media campaigns, and underwrites (and even establishes) patients’ groups.

Dr Healy stressed to this writer that he is not hostile to the industry, simply stating that its influence needs to be recognized.

During the 1990s, Dr Healy went on to say, we converted cases that would have been treated by Valium and Librium into cases treated by Prozac, Paxil, and Zoloft. Back in the 1960s, an Eli Lilly print ad for a tranquilizer showed a young mom playing with her daughter. Another Lilly ad from the same period, by contrast, displayed the face of depression as an elderly woman. Back then, he reminded his audience, depression was regarded as a rare illness affecting mainly older people. In 1996, when the World Health Organization reported that depression was the second greatest source of disability on the planet, the reaction from psychiatry was not how did society become depressed so fast, but rather "we’re the second most important people in medicine after the cardiologists."

But this trend was far from universal, Dr Healy pointed out. During the nineties, the Japanese did not become depressed the way we did. Prozac is not on the market there [Note: this has since changed], and tranquilizer use remains vastly greater than antidepressant use. Most of the rest of the world, Dr Healy reminded his audience, follows the Japanese model.

Which raises the $64,000 question: Are we better off with antidepressants? The answer may elude us, if we follow Dr Healy’s reasoning. Randomized clinical trials, he says, were never meant to prove a treatment works. Rather, they are designed to show something doesn’t work, as in the case of a charlatan promoting snake oil. It is industry’s "greatest achievement," claims Dr Healy, to turn this around. Although he does prescribe antidepressants in his clinical practice, one senses it is with the confidence of one recommending a Tylenol for unexplained pain than an antibiotic to knock out a particular infection. Indeed, he concluded, if SSRIs worked for depression or anxiety the way antibiotics do for GPI (syphilis), we wouldn’t have the illness around anymore.

Don’t expect this guy to be the guest of honor at any industry-sponsored symposia.

More

In his UCLA grand rounds lecture, and in an internet article, Dr Healy gave several examples of how pharmaceutical companies influence medical and public opinion. One of these involved the company, Current Medical Directives (CMD), which ghost-writes and coordinates medical articles for its clients. As part of a legal action against Pfizer, Dr Healy obtained access to a document that listed the progress of 85 articles on Zoloft. Two articles in preparation related to Zoloft and PTSD, for which Pfizer was seeking a license. The authors were listed as "TBD," for "to be determined." The articles eventually appeared in JAMA and the Archives of General Psychiatry, with several academic psychiatrists credited as the authors. In a study published in the British Journal of Psychiatry, Dr Healy found that the 85 CMD articles were cited three times more often than non-CMD Zoloft articles. One hundred percent of the CMD articles reported favorable results for Zoloft vs 44 percent of the non-CMD articles.

Another example involved six academic articles on pediatric depression, with the authors hailing Paxil as "effective, safe, and well tolerated," despite clear evidence of suicidal thinking and behavior in some patients, greater than those on the placebo and comparison drugs. Since then, citing the same data the academic authors had access to, authorities in the UK have advised against prescribing Paxil to patients under age 18 while the FDA in the US has announced strengthened warnings on product labeling.

Postscript: In 2004, following two highly-publicized public hearings, the FDA announced that black box warnings advising of increased suicidal risk for non-adults would appear on antidepressant product labeling.

Do Antidepressants Work?

In 2002, the July 2002 Prevention and Treatment published a study by Irving Kirsch PhD of the University of Connecticut. The study analyzed the FDA database of 47 placebo-controlled short-term clinical trials involving six antidepressants. These included "file drawer" studies, ie trials that failed but were usually never published.

The study found that the mean difference between the drug and placebo was a "clinically insignificant" two points on the HAM-D depression scale.

In other words, going solely on these data, there is no rational basis for choosing to take an antidepressant, much less for doctors to be prescribing them.

There are two main arguments to rebut this conclusion, both raised in an editorial in this month's American Journal of Psychiatry. In the editorial, Sanjay Matthew MD and Dennis Charney MD (both of the Mount Sinai School of Medicine) use findings from the NIMH-underwritten STAR*D real world clinical trials in support, namely:

"Mean" data is misleading in that it fails to parse out those populations who truly benefit from an antidepressant as opposed to those who don't. Clinical observation reveals that for certain patients an antidepressant is a Godsend. The catch is we don't know in advance which patients are more likely to respond.

STAR*D made an attempt at this, finding, amongst other things, that depressed people with anxiety or substance use, those with melancholic features, and those with a certain gene variation fare less well on antidepressants.

STAR*D also demonstrated the value of switching to a second antidepressant if the first one fails. The study showed that while at least half those in the study did not achieve a good result on their first try, according to the AJP editorial: "Patients who completed all phases of the study had an overall cumulative remission rate of 67%."

The editorial, however, failed to point out a major catch, namely that the 67 percent remission rate is theoretical, fully acknowledged by STAR*D. In the words of STAR*D's authors:

"The theoretical cumulative remission rate is 67% ... Note that this estimate assumes no dropouts, and it assumes that those who exited the study would have had the same remission rates as those who stayed in the protocol."

Ah, drop-outs. In the words of Holly Swartz MD of the University of Pittsburgh addressing a symposium at the 2006 American Psychiatric Association annual meeting: "If a patient doesn't stay on it, it doesn't do any good, even if it works."

The Kirsh study found a mean drop-out rate of 63 percent in it's review or clinical trials. This finding corresponds to other studies. In STAR*D, of 3,671 who entered the study only 123 made it to Round Four (keeping in mind that those who did well exited at earlier rounds).

Commenting on STAR*D, in a recent blog, Nassir Ghaemi MD of Tufts University noted that:

"Even if antidepressants worked in the short term (2 months, which is also what the meta-analysis assessed), one-half of patients who stayed on them relapsed into depression within one year. At the one year outcome, only about 25% of patients actually had remained well on and tolerated an antidepressant, much below the levels most clinicians seem to feel occurs in their clinical experience."

So what can we learn from all this?

First, beware of the exaggerated claims of the pharmaceutical industry and psychiatry. Also, beware of those making negative claims. All sides in this debate excel at spinning data.

Second - assuming you are not suffering from bipolar or a depression that behaves like bipolar - it is rational to choose to go on an antidepressant. Antidepressants may not work for everyone, but you may be one of the lucky ones.

Further, if your first antidepressant fails, it is worth persevering with a second or even a third antidepressant. Assuming you do not give up, your theoretical chance of success is two in three.

But also keep in mind you may find these meds intolerable and that relapse rates are high. They work in some cases, but they also disappoint. To conclude with Dr Ghaemi:

"We could all wish that clinicians' beliefs about antidepressants were true, or even half true. And perhaps they are the latter, for these agents surely have some uses in some settings; they are just not the dream drugs they seemed to be. ..."

From mcmanweb:

When Your Second Antidepressant Fails

The paradox: Perhaps if we don’t expect much of our antidepressant, we can get much better results.

Clinical Trials - What the Drug Companies Don't Report

So what is the most meaningful figure in an antidepressant trial? Apparently not the response rate, not the remission rate, not the Hamilton Depression scores. It's the drop-out rate, way too high whether going by industry figures or the FDA database. Clearly we are sending an unequivocally strong message that our medications leave much to be desired. Are any drug companies listening?